PROJECT SUMMARY The rising worldwide incidence of obesity is inflicting a massive toll on our healthcare system due to complications of type 2 diabetes, heart disease, and stroke. Recent evidence shows that chronic, low-grade inflammation is the causal link between obesity and its associated pathologies. Visceral adipose tissue is the initiating site, where pro-inflammatory macrophages are harbored in large numbers. These cells release cytokines that alter local and systemic physiology, inducing glucose intolerance, insulin resistance, and cardiovascular dysfunction. Therefore, pro-inflammatory macrophage cells in adipose tissue present an obvious target for clinical intervention. We recently developed a novel strategy to efficiently deliver therapeutic cargo to adipose tissue macrophages using polysaccharides delivered through the peritoneum. We observe exceptionally high targeting efficiency (up to 63% of the injected dose) in mouse models of obesity. Remarkably, when these polysaccharides are conjugated to anti-inflammatory prodrugs, a single dose reduces gene expression of pro-inflammatory cytokines both in adipose tissue and blood. The delivery vehicle (polysaccharides), linkers, and drugs are all FDA-approved such that these compounds could potentially be rapidly translated to clinical testing. The goal of this proposal is to thoroughly and rationally develop these nanomaterials-based prodrugs through mechanistic studies to understand the delivery process and the physiological impact. We will perform quantitative biodistribution, cellular uptake, and multiscale imaging studies to maximize delivery efficiency and further widen the therapeutic window. We will further apply cellular and genomics assays in rodent models of obesity to test efficacy toward reducing local and systemic inflammation, diabetic phenotype, and off-target side effects that are expected to be minimized compared with free drug counterparts. Finally, we will optimize the delivery rate using chemical linkers and controlled-release formulations to to generate a lead compound ready for translational studies by the conclusion of the award period. Our highly multidisciplinary team is well suited to succeed in all aspects of this proposed work. Our team includes experts in nanomaterials chemistry (Andrew Smith), animal models of obesity and diabetes (Kelly Swanson), macrophage and obesity biology (Erik Nelson), quantitative imaging and biodistribution (Wawrzyniec Dobrucki), veterinary pathology (Matthew Wallig), and translatable controlled release materials (Benjamin Keselowsky). Success in this proposal will specifically provide a new therapy that can decouple obesity from its comorbidities by inhibiting systemic inflammation, and more broadly yield families of anti- inflammatory compounds with widened therapeutic windows due to high delivery efficiency to specific cells and tissues. This preventative therapeutic strategy may similarly benefit patients suffering from the ever-expanding list of diseases for which systemic inflammation is causally implicated.